2-(4-biphenylyl)-tetrahydrofurans

ABSTRACT

2-(4-BIPHENYLYL-TETRAHYDROFURANS OF THE FORMULA   WHEREIN R1 is hydrogen or halogen; as well as methods of combatting inflammation utilizing an antiphlogistic amount of the 2-(4-biphenylyl)-tetrahydrofurans.

United States Patent Seeger et a1.

( 1 Aug. 26, 1975 2-( 4-BIPHENYLYL )-TETRAHYDROFURANS Inventors: Ernst Seeger; Helmut Teuiel;

Wollhard Engel; Josef Nick], all of Biberach an der Riss Germany Boehringer Ingelheim GmbH, lngelheim am Rhein- Germany Filed: Aug. 13, 1973 Appl. No.: 387,803

Assignee:

Foreign Application Priority Data Aug. 17. i972 Germany i. 2240438 References Cited UNITED STATES PATENTS 8/i94l Reppe et al 260/3461 Primary Examiner-Harry I. Moatz Attorney, Agent, or FirmHammond & Littell [57] ABSTRACT 2-(4-biphenylyll-letrahydrofurzms of the formula wherein R is hydrogen or halogen; as well as methods of combatting inflammation utilizing an antiphlogistic amount of the 2-(4-biphcnylyl)-tetrahydr0furans.

4 Claims, No Drawings 2- 4-BIPHENYLYI,l-TETRAHYUROFI'RANS ()BJIiCTS OF 'I'Hli INVENTION An object of the present invention is the develop ment of novel antiphlogistically active 3-(4- biphcnylyl )-tetrahydrolurans.

Another object of the invention is the development ot a compound ol the formula wherein R, represents a member selected from the group consisting of hydrogen and halogen.

A further object of the invention is the development of a method ofcounteracting inflammation in a \varmbloodcd animal. which comprises administering to said animal an effective antiphlogistic amount ol one or more 01 the above 2-( 4-biphcnylyl )-tetrahydrol'urans.

These and other objects otthe invention will become more apparent as the description thereol proceeds.

DESCRIPTION OF THE INVENTION The invention relates to new 2-t4-biphenylyl) tetrahydrofurans of General Formula I.

\J L, l

Method A A 4(4-biphenylyll-l.4-butandiol of General Formula Il.

R1 OH I CH-CH2- CH -CHg-OH vvhcrvvin R, is as hereinbel'ore delined. is treated with a cyclodchydrating agent at temperatures between l0 and 250C.

The reaction may be carried out in the absence of a solvent Preferably. however. the reaction is carried out in the presence of an inert water-immiscible solvent. Suitable solvents include hydrocarbons like benzene. toluene or xylene. In some cases it is of advantage to operate at reflux using a water separatory condenser. The preferred reaction temperature is between and The cyclodchydrating agents which may be used are. for example. inorganic or organic acids. such as phos phoric acid. sulfuric acid. p-tolucncsullonic acid. oxalic acid. or acidically reacting salts like potassium hydro gen sulfate or hydrogen halide salts ol pyridine. as well as anhydrous metal salts like 7.inc chloride or also sullonic acid halogenides in the presence ol tertiary organic bases like pyridine or cationic exchanger resins. containing sultonic acid groups.

When using pyridine hydrochloride and ptoluenesull'onic acids. 4-( 4-biphenylyl )-3-butenols may be obtained as by-products. which may be removed by column chromatography.

The starting compounds ot General Formula II may. for example. be obtained by reduction ol 4-( 4- biphenylyl l-4oxo-butyric acid esters with complex hydridcs. Especially lithium aluminum hydride at room temperature and in the presence of a suitable solvent. cg. diethylcther or diosane. may be used. The starting compounds of General Formula Il are further described in the copending US. Pat. application Ser. No. 395.880. filed Oct. It). 1972.

Method B The compounds of General Formula I may also be prepared by cyclization ol 4-(4-biphenylylJ-hutenols otGeneral Formula I.

(III) wherein R, is defined as above. by means of acid agents at temperatures between 50 and 200C.

Especially suitable as acid agents are sulfuric acid. p-toluetiesult1iiiic acid. potassium hydrogen sulfate and zinc chloride. In some cases it might be advantageous to carry out the reaction in an inert solvent such as toluene. xylene or benzene. The starting compounds of General Formula I] may be obtained. for example. from correspondingly substituted 4-(4-biphenylyl)-3- butenoic acids by catalytic reduction ofthe carboxyl by means of complex hydrides such as lithium-aluminum hydride. lithium boron hydride. sodium-bis-(Z- 3 mcthoxy-ethoxy)-dihydroaluminate. in tetrahydrofuran at room temperature.

The 4-(4-biphenylyl)-3-butenoic acids may themselves be prepared. for example. by splitting off of water from corresponding well known 4-(4- biphenylyll-4-hydroxybutyric acids in the presence of hydrogen halide salts of tertiary organic bases. The splitting off of water can be effected at temperatures between l40 and 200 C. The tertiary organic bases which maybe used are. for example. pyridine and alkyl pyridines. The hydrogen halide utilizable is. for exampic. hydrogen chloride. The 4-(4-biphenylyli-3- butenoic acids are further described in the copending US. Pat. application Ser. No. 289.008. filed Sept. I4. 1972. and the starting compounds of General Formula iii are further described in the copending US. Pat. application Ser. No. 387.802. filed concurrently herewith. now U.S. Pat. No. 3.859.256. As already above mentioned. the compounds of General Formula I have valuable pharmacological activities. especially a good antiphiogistic activity. The compounds of General For mula i may also serve as starting materials for the preparation of antiphlogistically active 4-(4-biphenylyl)- butanols. e.g. 4-(2'-fluoro-4-biphenylyl)-butanol.

For pharmaceutical application. the new compounds of General Formula I may be incorporated into the usual pharmaceutical compositions. optionally in combination with other active ingredients of General For mula l. The single dose amounts from 50 to 400 mg. preferably from I to 300 mg. the daily dose amounts from 100 to L000 mg. preferably from [50 to 600 mg.

The following examples further illustrate the invention without being limitative in any manner.

EXAMPLE I 2( 2'-Fluoro-4-biphenylyl )-tctrahydrofuran by Method A (1.5 gm (0.025 mol)of l-(2-fluoro-4-biphenylyl)-l.4 butandiol (m.p.: 87 to 88C were refluxed for 30 min utes with 0.5 gm of p-toluenesulfonic acid in 80 ml of toluene using an apparatus incorporating a water separatory condenser. After cooling. the mixture was diluted with ether. washed with water. then washed with sodium hydrogen carbonate solution and again with water. dried over sodium sulfate and the solvent was distilled off. The remaining residue was distilled (b.p. l30 to l3lC). The 2-(2'-fluoro-4- biphenylyl)-tetrahydrofuran crystallized and melted after recrystallization from petroleum ether at 34 to 35C yielding 5.6 gm (92.4 percent of theory). it was identified to be the compound of the formula 2-(2Fluoro-4-biphenylyll-tetrahydrofuran (1.5 gm (0.025 mol) of l-(2'-fluoro-4-biphcnylyl-l .4- butandiol were refluxed for 30 minutes in 80 ml of henzenc under addition of 3.8 gm (0.025 mol) of anhy 4 drous zinc chloride using an apparatus incorporating a water sepuratory condenser. The further processing is described in Example l. The tetrahydrofuran was obtained of mp. 34 to 35C in a yield of 89.2 percent of theory.

EXAMPLE 3 2-( 2'-Fluoro-4-biphcnylyl i-tetrahydrofuran Preparation according to Example 2. however. by use of0.2 ml of 89 percent phosphoric acid. yielding tetrahydrofuran of m.p. 34C (97.5 percent of theory).

EXAMPLE 4 2-12'-Fluoro-4-biphenylyi)-tetrahydrofuran 6.5 gm (0.025 mol) of i-( 2'-fluoro-4-biphenylyl)- l.4-butandiol together with 0.2 ml of concentrated sulfuric acid dissolved in ml of benzene were refluxed for 10 minutes and the mixture was then treated as described in Example 1. yielding 5.6 gm (92.6 percent of theory) of 2-( 2'-fiuoro-4-biphenylyl )-tetrahydrofuran of mp. 33 to 34C.

EX A MPLE 5 2-( 2'-Fluoro-4-biphenylyl-tetrahydrofuran 13 gm (0.05 mol) of l-(2-fluoro4biphcnylyl)'l.4- butandiol were dissolved in l50 ml of absolute toluene. then refluxed for 30 minutes under addition of 6.8 gm (0.05 mol) of potassium hydrogen sulfate using an apparatus incorporating a water separatory condenser and treated as in Example 1.

Yield: l0 gm (82.6 percent of theory) of 2-(2'- fluoro4 biphenylyl Hetrahydrofuran of b.p.., to l3lC (m.p.: 33 to 34C).

EXAM PLE 6 2-( 4 l3iphenylyl i-tetrahydrofuran I82 gm (0.075 mol) of l-(4-biphcnylyl)-l .4- butandiol (mp. 79C) and l0.2 gm (0.075 mol) of potassium hydrogen sulfate were refluxed for 30 minutes in ml of absolute toluene using an apparatus incorporating a water separatory condenser. The preparation was then effected according to Example I.

Yield; 10 gm (59.4 percent of theory) of 2(4- biphenylyl )-tetrahydrofuran ofbp 122 to l23C it was identified to he the compound of the formula EXAMPLE 7 2-( 2-Chloro-4-biphenylyl Hetrahydrofuran 8.3 gm (0.03 mol) of l-(2'Chloro-4-biphenylyl l .4- butatidiol (mp. 88 to 89C) were refluxed for 1 hour in 200 ml ofabsolute toluene with 4.1 gm of potassium hydrogen sulfate using an apparatus incorporating a water separatory condenser. The preparation is carried out as described in Example I.

Yield: 6.5 gm 87 percent ofthcory of 2( 2'-Chloro- 4-biphenylyl)-tctrahydro|'uran oi lw.p.., l33C and m.p. 52to 53C (from petroleum ether). it was identified to be the compound of the formula EXAMPLE 8 2-( 2 '-Fluoro-4-biphcnylyl )-tetrahydrofuran 3.25 gm t0.0l mol) of l-(2'-fluoro-4-biphenylyl)- l.4-butandiol were refluxed for minutes with 2.48 gm (0.0l 3 mol) of p-toluene-sull'onic acid chloride and l.ll gm (0.014 mol) of pyridine in 80 ml of absolute toluene. The residue. obtained after distilling off of the solvent. was dissolved in 100 ml of methanol and this solution was made strongly alkaline by addition of 20 percent sodium hydroxide solution. After standing for 2 hours at room temperature. the reaction mixture was poured into water and extracted with ether. The solvent was distilled off from the ethereal solution. which had been washed with water and dried. whereby the 2- t2-fluoro-4-biphenylyl)-tetrahydrofuran (mp 33 to 34C) was obtained.

Yield: L8 gm (59.5 percent oftheory) EXAMPLE 9 2-( 3 '-Chloro-4-biphenylyl )-tetrahydrofuran 12.2 gm [0.044 mol) of l(3'-chloro-4-biphenylyl)- l.4-hutandiol were heated for 2 hours with 7.5 gm

((1.055 mol) of potassium hydrogen sulfate in I30 ml of xylene using an apparatus incorporating a water separator condenser. The organic salt was filtered off while hot and the filtrate was dried. The residue was distilled in vacuo. whereupon the desired product was obtain (b.p.. 158 to l65C) which was subsequently recrystallized from petroleum ether. yielding 9.0 gm (79.2 percent of theory) of 2-( 3-chloro-4biphenylyl tetrahydrofuran of m.p. 46 to 465C. it was identified to be the compound of the formula EXAMPLE l0 2-[ 2Fluoro4-biphenylyl )-tctrahydrol'uran by Method B l0 gm. of 4-(2'-fluoro4-biphcnylyl)-3-buten-l-ol (mp. 79 to 80C) were heated for 3 hours up to l00C with 209 ml of 30 percent sulfuric acid while stirring. Then about 200 ml of water were added and the mixture was extracted twice with l()() ml of ether each time. The ethereal solution was washed with water sev eral times. dried and filtered on charcoal. The solvent was distilled off. the remaining residue was triturated with petroleum ether. whereby the 2-( 2'-llaoro--$- biphenylyll-tetrahydrofuran dissolved in the petroleum ether and the unreacted solid starting compound may be filtered off. The solvent was removed from the petroleum ether solution. After the residue had been distilled. l.5 gm of 2-(2'-l'luoro-4-biphenylyl)- tetrahydrofuran were obtained (b.p.., ..l45 to l47Cl which crystallized after a short time and melted at 34 to 35C.

EXAMPLE I l 2-( 2'-Fluoro-4-biphenylyl )-tetrahydrofuran 1 gm. (0.004] mol) of 4-(2'-fluoro-4-biphenylyl)-3- butcnl -ol were refluxed for 8 hours in 20 ml of toluene by addition of (H gm of p-toluenesulfonic acid. After cooling. the mixture was diluted with ether. the solution was washed with water. dried over sodium sulfate and the solvent was distilled off. The remaining oily residue was distilled to medium high vacuum. The abovementioned tetrahydroftiran was obtained of hp... l45 to l-l7C in a yield of 0.6 gm (60 percent of theory).

EXAMPLE 1'.

2-( 2'-Fluoro-4-biphenylyl )-tctrahydrofuran 2.42 gm (0.01 mol) of -l-(2'-fluoro-4biphenylyl)-3- buten-l-ol were refluxed for 13 hours in 60 ml of absolute toluene after addition of L2 gm of potassium hydrogen sulfate. After cooling. water and ether were added. the organic solution was washed with water. dried over sodium sulfate and the solvent was distilled off. The remaining solid residue was triturated with petroleum ether and filtered. The solvent was removed from the petroleum ether solution and the remaining oily residue was distilled in medium high vacuum. 0.2 gm (8.25 percent of theory) of the above-mentioned tetrahydrofuran were obtained (hp... 144 to 145C). The same result is obtained if xylene is used instead of toluene.

EXAMPLE l3 2-( 2-Fluoro-4-biphenylyl )-tctrahydrofuran 2.42 gm (0.01 mol) of 4-(2'-tluoro-4'hiphcnylyll-3 buten-lol were refluxed for 7 hours in 30 ml of henzene after addition of 2 drops of concentrated sulfuric acid. After cooling. water and ether were added and the organic layer was separated. The organic solution was washed with water. dried. filtered on charcoal and the solvent was distilled off. Petroleum ether was added to the remaining oil. whereby the unreactcd starting compound crystallized. which was subsequently l'il tered off. The solvent was removed from the petroleum ether solution and the remaining residue was distilled in vacuo. 0.4 gm 16.5 percent of theory) of the abovemetioned tetrahydrofuran top... l44 to 145C) were obtained.

EXAMPLE l4 Pharmacology The following substances were tested with regard to their absolute antiphlogistic activity and their toxicity:

t 2 'l-luoro-4-biplienylyl l tetrahydrofuran J-BiphenylylJ-teirahydrol'uran l 2 '-Chloro4-biphen \lyl )-telrahydrofuran 7 The compounds were tested in respect to their antiexudative effect on the kaolin-induced edema and the earrageenin-induced edema of the hind paw of the rat and in respect to their acute toxicity after oral applicad. lherapeutic Index The therapeutical indices (a measure of the thera peutic usefulness) ere calculated as the quotient of tion to rats. in comparison with pheny lbutazone. the LO value divided by the ED- value deriving from the tests re ardin the anti-exudative activity a tinst a. kaolin-induced edema oi the hind paw ot the rat l E b 4 the Laolin and carrageenin edemas.

The kaolin edema was induced according to the The results obtained from these tests are shown in the method given by HILLEBRECHT (Anneimittel following Table l. The above-mentioned compounds Forsch. 4. 607 l 1954 )by subplantary injection of 0.05 surpass the known compound phenylbutazonc in their in] of a ll) percent suspension of kaolin in a 0.85 perantiphlogistic activity. cent sodium chloride solution. Measuremennt of the As the toxicity does not run parallel with the antivolume ofthe paws was effected using the technique of phlogistic activity. the compounds concerned have a DOEPFNER and CERLETTl (lnt. Arch Allergy therapeutic index of at least twice that of phenylbutalmniunol. 12.89 (1958)). l5 70th..

TABLE 1 ('ompound kaolin edema carrageenin awrage acute toueity therapeutical index El) per os edema \alue in the rat Til) per os El) mg/kg confidence ratios gi\en by the mgikg mgfkg lag/kg limits tone and antiexudti- (95"; probthe acti\it) ilhlllfll L lll iifi Phenylbutalone 58 (W 63.5 K64 793 7 J42 l3.b "A m5 20.x 713 536-948 34.3 I! .13 46 39.5 em (to i 1247 23.0

c 37 in 43 5 |stiti 2| -t|.3

3| after application ot lttlttl mgikg per its. 1 out of H ilttlttmls tlietl The l\u| compound v-eitesaniined .is solution in sesame oil in all test Male FW 49 rats having an average weight of 120 to l50 gm were fed with the test compounds minutes before inducing the edema by means of an oesophagcal tube. Five hours after the provocation ofthe edema the averaged values of the swelling caused in the rats treated with the test compounds were compared with values measured on control animals. By graphical extrapolation. the dose leading to a percent reduction of the swelling ED;. was calculated from the percentage reduction values measured by the administration of different doses.

b. Carrageenin-induced edema of the hind paw of the rat The provocation of the carrageenin edema was ef fected according to the method of WINTER et al. (Proc. Soc. exp. Biol. Med. H1. 544 tl9b2l)by subplantary injection of 0.05 ml of a l percent solution of carrageenin in a 0.85 percent solution of sodium chloride. The test compounds were administered 60 min utes before the provocation of the edema. For the caleulation of the reductive effect on the edema. the values measured 3 hours after the provocation of the edema were used. All the other details were the same as described above in the case of the kaolin-induced edema.

c. Acute toxicity After oral administration to male and female FW 49 rats (ratio 1:] )having an average weight of l35 gm. the acute toxicity (LD was determined. The compounds were fed as a trituation in Tylose. The calculation of the LD values was effected. as far as possible. according to the method of LITCHFIELD and WILCOXON. based on the percentage of animals which died within 14 days after administration of the different doses.

(ill

For pharmaceutical purposesthc compounds according to the present invention are administered to warmb loodcd animals perorally or parentcrally as active in gredients in customary dosage unit compositions. that is compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient. such as tablets. coated pills. capsules. wafers. powders, solutions. suspensions. emulsions. syrups. suppositories and the like. One effective antiphlogistic dosage unit of the compounds according to the present invention is from 0.83 to 6.67 mgm/kg body weight. preferably l.33 to 5.0 mgm/kg body weight. The daily dose rate is from L66 to I67 mgm/kg body weight. preferably 2.5 to [0 mgm/kg body weight.

The following examples illustrate a few pharmaceuti cal dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modcs contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 15 Tablets with 200 mg of 2-( 2'-fluoro-4-biphenyly l l-tetrahydrofuran Composition:

1 tablet contains;

Acme ingredient 200 0 mg ('orn starch )7 0 mg Polyunylpyriolitlone llll) mg Magnesium sletiratc 3.0 mg

310th mg Method of preparation ll 2 '-fluoro-4-biphenylyl )-tetrahydrofuran was mixed with corn starch. granulated with a 14 percent solution of polyvinylpyrrolidone in water. passed 9 through a screen of 1.5 mm. dried at 45%. and passed once more through the said screen The granulate thus obtained as mixed with magnesium stearate and pressed into tablets. Weight of tablet: 310 mg Punch:

10 mm flat.

EXAMPLE 1(\ Coated tablets with 200 mg of 3-1 I'-t1uoro-4-biphenylyl )teti'ahydrofuran Composition:

1 coated tablet core contains;

.\cti\c ingredient 100.0 mg (orii starch 70 mg tielaiiiie s 0 mg lalcuin 18.0 mg Magnesium stearalc 40 me Method of preparation:

The mixture of the 2-1Z-tluoro-4-hiphenylyl)- tetrahydroluran and the corn starch was granulated with an aqueous percent solution of the gelatine through a 1.5 min mesh screen. dried at 45C and again passed through the screen. The granulate thus obtained was mixed with the talcum and the magnesium stearate. and the resulting composition was compressed into coated tablet cores.

Weight of core: 300.0 mg Punch: 10 mm flat The coated tablet cores were subsequently coated according to known processes with a thin shell consisting essentially of a mixture of talcum and sugar and finally polished with beeswax.

Weight of the coated pills: 580 mg.

EXAMPLE l7 Gelatine capsules with 200 mg of 2-( 2 '-l1uoro4biphenylyl l-tetrahydrofuran Composition:

1 gelatinc capsule contains:

Active ingredient 200.0 mg Lorn starch I90 0 mg (olloidal IslllLlL acid 6.0 mg Magnesium stearate 4.0 mg

Method of preparation The substances were intimately mixed and filled into No. l gelatine capsules. 1 gelatine capsule contains: 400 mg of preparation and 200 mg of Z-tT-fluoroA- biphenylyll-tetrahydrofuran. an oral dosage unit with an effective antiphlogistic action.

EXAMPLE: 18

Suppositories with 300 mg of 2-1 4biphenylyl l-tetrahy drofuraii Composition:

1 suppository contains:

-continued (c g itepsol 451 1450.0 mg

M ethod of preparation The finely pulverized 2-1 4-biphenyl l-tetrahydi'ofuran was stirred into the molten suppository mass and. after cooling to 40C. was blended by means of an immersion homogenizer and poured into slightly precooled molds at 38C.

Weight ofsuppository: 1.75 gm.

EXAMPLE 1) Suspension with 200 mg of Z-( 4-bipheiiylyl l-teti'aliydrofuraii Composition:

Acme ingredient 4.0 gm l)ioct \1 sodium sultosuecinale tDUXSSI 0.01 gm lien/inc acid I) 1 gm Sodium cyclaiiiate 0 I gm Colloidal \tliClL' acid l 0 gm Poly\inylpyi'rolidonc 0.1 gm (ilyccrinc Z5 0 gm Grapefruit l1a\oring 0.1 gm Di tilled .itct' rid lllllll ml EXAMPLE Z0 Coated tablets with mg of 2( 4-biphenylyl l-tetrahydroturan Composition:

.-\cti\e ingredient 1000 mg Lactose 55.0 mg

Corn starch 41.0 mg

Pol}vinylpyrrolidone 2.0 mg

Magnesium sleariite 1.0 mg 200.0 mg

Method of preparation The mixture of 1-(4-biphenylyl )-tetrahydro1uran with lactose and corn starch was granulated with an aqueous 8 percent solution of the polyvinylpyrrolidone through a 1.5 mm mesh screen. dried at 45C and again passed through a screen of 10 mm mesh size. The grair ulate thus obtained was mixed with magnesium stearate and compressed into coated tablet cores.

Weight of core: 200 mg Punch: 8 mm. arched The coated tablets were coated according to known processes with a thin shell consisting essentially of a wherein R represents a member selected from the group consisting of hydrogen and halogen.

2. The compound ol claim I which is 2-( 2'-fluoro-4- biphenylyl l-tetrahydrol'uran.

which 2-(4- 3. The compound oi claim 1 is hiphenylyl l-tetrahydrol'uran,

4. The compound of claim I which is 2-(Z'-chloro-4- hiphenylyl)-tetrahydrol'uran. 

1. A COMPOUND OF THE FORMULA 4-(TETRAHYDROFUR-2-YL),R1-BIPHENYL WHEREIN R1 REPRESENTS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND HALOGEN.
 2. The compound of claim 1 which is 2-(2''-fluoro-4-biphenylyl)-tetrahydrofuran.
 3. The compound of claim 1 which is 2-(4-biphenylyl)-tetrahydrofuran.
 4. The compound of claim 1 which is 2-(2''-chloro-4-biphenylyl)-tetrahydrofuran. 